DE NOVO FATTY ACID SYNTHESIS BY MICROSOMAL ELONGASES IN TRYPANOSOMES

Fatty acids (FAs) up to palmitate (C16) are made de novo by type I synthases in mammals and fungi. Bacteria and plants use type II synthases to make up to stearate (C18). Both systems are soluble, cytosolic, and depend on acyl-carrier protein to ferry the growing acyl-chain. The bloodstream form of Trypanosoma brucei, a parasite causing sleeping sickness, mainly synthesizes myristate (C14) for variant surface glycoprotein glycosylphosphatidylinositol (VSG GPI) anchors. The VSG forms a dense surface coat that is periodically replaced to evade destruction by the host immune system. In contrast, insect vector trypanosomes (procyclic forms) make longer FAs for phospholipids and do not myristoylate their GPIs. The type of FA synthesis system in trypanosomes and how it produces these different products in the two life-cycle stages is unknown. Here we describe the trypanosome's unusual FA synthesis machinery involving CoA-dependent FA elongases in the ER. Elongases 1–3 extend butyryl-CoA (C4) stepwise to caproyl-CoA (C10), myristoyl-CoA, and stearoyl-CoA (C18), respectively. The entire pathway is up-regulated during growth in medium depleted of FAs allowing for adaptation to changing environments. In other eukaryotes, elongases do not make FAs de novo; instead they extend pre-existing long-chain FAs. Our results demonstrate a third type of de novo FA synthesis system distinct from conventional type I and type II pathways.